Hematopoietic failure is the major cause of death in Acute Radiation Sickness. Unfortunately, few therapies exist that are effective at mitigating radiation-induced damage to the hematopoietic system. We hypothesized that cells within the bone marrow microenvironment, specifically endothelial cells (ECs), regulate hematopoietic regeneration following radiation injury. Our recent studies validated this hypothesis, demonstrating that human ECs produce soluble proteins that induce the expansion of human hematopoietic stem cells (HSCs) in vitro and transplantation of ECs alone rescued animals from lethal radiation exposure and accelerated hematopoietic reconstitution in vivo. A genetic screen revealed pleiotrophin (PTN), a heparin binding growth factor with no known function in hematopoiesis, as 25-fold overexpressed in ECs with HSC-supportive activity. Our preliminary studies demonstrate that treatment with PTN induces a 10-fold expansion of murine HSCs in culture and systemic administration of PTN to irradiated mice demonstrates that PTN treatment markedly accelerates reconstitution of BM HSCs and progenitor cells compared GCSF- or saline-treated controls. We hypothesize that PTN regulates the selfrenewal and regeneration of BM HSCs in vitro and in vivo and that PTN is an excellent candidate mitigator of radiation-induced hematopoietic failure. In order to test our hypothesis, we propose the following Specific Aims: 1) Determine the function of PTN in regulating HSC self renewal and homeostasis. 2) Determine if PTN can mitigate radiation-induced myelosuppression in vivo, and 3) Test the efficacy of PTN in mitigating human hematopoietic cell toxicity from radiation injury. Our broad objective in this proposal is to deliver a translatable and potent mitigator of radiation-induced hematopoietic injury. Our preliminary results demonstrate that PTN is a soluble growth factor for murine and human HSCs and systemic administration of PTN for 1 week induces the accelerated regeneration of BM HSCs and progenitor cells in vivo compared to GCSF-treated mice. PTN has therapeutic potential as a mitigator of the radiation-induced hematopoietic syndrome.